Large meta-analysis confirms efficacy of statins in primary CVD prevention, but individual benefit-harm profiles vary
Comparative effectiveness and safety of statins as a class and of specific statins for primary prevention of cardiovascular disease: A systematic review, meta-analysis and network meta-analysis of randomized trials with 94,283 participants
Introduction and methods
The role of statins for primary prevention of CV events is highly debated [1-4]. Some see great potential for statins to reduce the burden of CVD and they recommend life-long use of statins for many healthy individuals [5-8]. Others argue that the evidence-base and decision support for individuals and health care professionals has not yet been developed enough.
Current guidelines used data obtained from systematic reviews and meta-analyses. However, these studies often suffer from limitations. Several meta-analyses reported effects of statins on composite outcomes only, while statins may have opposite effects for certain outcomes and their effect size on different outcomes may vary substantially [9-11]. Various systematic reviews examined statins as a class, which may conceal differences in efficacy and safety between individual statins . Moreover, some of the systematic reviews mixed primary and secondary prevention populations, even though effects might differ between these groups. Plus, primary prevention populations are often prescribed low-dose statins [3,13,14].
To inform the debate on statins, a comprehensive systematic review, meta-analysis and drug-level network meta-analysis of RCTs was conducted (January 2013 – November 2018) to estimate the effectiveness and safety of statins as a class and of individual statins for primary prevention of CVD. Eligible open-label or double-blind RCTs (40 trials; n=94.283) compared a statin vs. placebo (33 trials) or a statin vs. another statin (7 trials) and reported results on at least one benefit or harm outcome in people without history of any CVD events at baseline (median age: 58.3 years). Six statins were considered: simvastatin, lovastatin, fluvastatin, atorvastatin, pravastatin, and rosuvastatin. Median follow-up was 1 year. Primary outcomes were CVD events or all-cause mortality.
Effects of statins on benefit outcomes
- Risk of non-fatal MI was significantly reduced with statins as a class (RR: 0.62, 95%CI: 0.53-0.72, I²=28.6%), compared to placebo. In the drug-level network analysis, non-fatal MI events were significantly reduced with atorvastatin, rosuvastatin and pravastatin, but not with lovastatin. Most effective treatment was observed with atorvastatin.
- Risk of fatal MI was significantly reduced with atorvastatin, while the other specific statins as well as statins as a class (RR: 0.72, 95%CI: 0.50-1.03, I²=0%) did not show significant effects.
- Statins as a class reduced the risk of non-fatal stroke (RR: 0.83, 95%CI: 0.75-0.92; I²=0). In the drug-level analysis, only the effect of rosuvastatin and atorvastatin were statistically significant.
- Neither statins as a class (RR: 0.79, 95%CI: 0.53-1.19; I²=0), nor individual statins had a significant effect on fatal stroke.
- All-cause mortality was significantly reduced with statins as a class (RR: 0.89, 95%CI: 0.85-0.93, I²=0%), compared with placebo. Individually, pravastatin, atorvastatin, and rosuvastatin showed statistically significant risk reductions of all-cause mortality.
- CVD mortality was significantly reduced with statins as a class (RR: 0.80, 95%CI: 0.71-0.91, I²=35.2%), compared with placebo. However, in drug-level analysis, only the effects of rosuvastatin and pravastatin on CVD mortality were significant.
- Fewer events of unstable angina were observed with statins as a group (RR: 0.75, 95%CI: 0.63-0.91, I²=0%), compared with placebo. However, in drug-level analysis, only the effect of atorvastatin reached statistical significance.
- Neither statins as a class (RR: 0.84, 95%CI: 0.71-1.02, I²=0%) nor individual statins significantly reduced the risk of HF, compared to placebo.
- The composite outcome of all major CV events (excluding fatal stroke, HF, and all-cause mortality) was significantly reduced with statins as a class (RR: 0.74, 95%CI: 0.67-0.81, I²=0%), compared with placebo.
Effects of statins on harm outcomes
- Both relative and absolute risk of myopathy were significantly increased with statins as a class (RR: 1.08, 95%CI: 1.01-1.15, I²=1.15%), compared with placebo. However, none of the statins individually showed a significant effect.
- Statins as a class did not have significant effects on T2DM (RR: 1.04, 95%CI: 0.91-1.19). However, subjects randomized to atorvastatin and rosuvastatin showed more diabetes events, compared with placebo.
- Hepatic dysfunction was increased with statins as a class (RR: 1.16, 95%CI: 1.02-1.31, I²=0%), compared with placebo. In drug-level analysis, fluvastatin reached statistical significance with a five-fold higher risk, compared with placebo.
- Relative risk of renal dysfunction was higher with statins as a class (RR: 1.14, 95%CI: 1.02-1.29, I²=4.6%), compared with placebo. In drug-level analysis, only the effect of rosuvastatin was statistically significant.
- Neither statins as a class, nor individual statins significantly affected treatment discontinuation due to adverse events, cancers, and headache and nausea, compared to placebo.
This systematic review, meta-analysis and network meta-analysis of RCTs on statins demonstrated efficacy both of statins as a class and of specific statins in prevention of CV events and all-cause mortality in primary prevention populations. However, increased risk of myopathy, renal dysfunction and hepatic dysfunction were observed. The benefit-harm profiles differed among individual statins. Atorvastatin and rosuvastatin appeared to be the most effective and atorvastatin the safest statin across most of the outcomes.
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